Inhibitors of sex steroid biosynthesis and methods for their production and use

ABSTRACT

Certain steroidal and non-steroidal compounds have been found to inhibit androgen and estrogen formation. Such inhibition may aid in the reduction of the activity of these hormones and may be useful in the treatment of diseases where, for example, inhibition of androgen or estrogen acitivity is desired. Preferred inhibitors also possess antiestrogenic activity, thus providing the advantage of a double inhibitory action both on estrogen formation and on estrogen action.

This is a continuation of application Ser. No. 07/322,154 filed on Mar.10, 1989, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to methods for inhibiting sex steroid formationand in particular to novel methods for inhibiting androgen and estrogenformation in vivo in warm-blooded animals, including humans.

For a number of years, there has been research for compounds which canefficiently inhibit androgen and/or estrogen formation (e.g. enzymeinhibitors) or for compounds which may suppress androgen or estrogenaction (steroid antagonists), without casuign adverse effects to healthytissues.

Recently, estradiol derivatives bearing a carboxyalkyl substituent atthe 7α-position maintained their affinity for the estrogen receptor whenlinked via their carboxy group to agarose or polyacrylamide resin foraffinity chromatography purification of the estrogen receptor (Bucourtet al., J. Biol. Chem. 253: 8221, 1978). It was subsequently found thatcertain 7α-substituted derivatives of estradiol possess antiestrogenicactivity (Bowler et al., 1985, Eur, Patent Application 0138504; Wakelingand Bowler, J. Steroid Biochem. 30: 141-147, 1989).

Non steroidal compounds bearing a similar aliphatic side chain have alsobeen found to possess antiestrogenic activity (U.S. Pat. No. 4,732,912).

Some steriod derivative, such as especially 16-methylene estradiol and16-methylene estrone, have been described as inhibitors of17α-hydroxysteroid dehydrogenase activity (Thomas et al., J. Biol. Chem.258: 11500, 1983).

Prior art methods have not been completely effective in inhibiting sexsteriod synthesis while avoiding undesirable side effects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the inhibitory effect of N-butyl,N-methyl-11-(16'α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl) undecanamide ("EM 139") on17β-hydroxysteroid dehydrogenase activity at different concentrations.

FIG. 2 is a graph showing the inhibitory effect of17β-hydroxy-17α-(12-iododecynyl)-Δ⁴ -androsten-3-one ("EM 150") on17β-hydroxysteroid dehydrogenase activity at different concentrations.

FIG. 3 is a graph showing the inhibitory effect of N-butyl,N-methyl-12,13-bis(4-hydroxyphenyl)-12-pentadecenamide ("EM 142") on17-hydroxysteroid dehydrogenase activity at different concentrations.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide methods foreffective inhibition of sex steroid formation.

It is another of the invention to provide methods for effectiveinhibition of estrogen biosynthesis in vivo in warm-blooded animals.

It is another object of the invention to provide methods for effectiveinhibition of androgen biosynthesis in vivo in warm-blooded animals.

It is another object of the invention to provide noval compositions forinhibition of sex steroid formation.

It is another object of the invention to provide composiions which actboth as sex hormone antagonists and as inhibitors of sex hormoneproduction, and methods for utilizing such compositions.

It is another object of the invention to provide inhibitors of sexhormone formation which are cost efficient to produce.

These and other objects may be achieved by providing a method forinhibiting sex steroid formation in a warm-blooded animal, includingman, by administering a therapeutically effective amount of a compoundof the formula: ##STR1## wherein the dotted lines represent optionaldouble bonds; wherein the A-ring is optionally aromatic;

wherein R₁, R₂ and R₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, alkylsulfonyl (lower) alkoxy,arylsulfonyl (lower) alkoxy, halogen, lower alkyl, lower alkoxy, loweralkylsilyl, amino and nitro;

wherein R₃ is selected from the group consisting of hydrogen, hydroxyl,halogen, lower alkyl, methoxy, ethoxy, propoxy, hydroxyethoxy, loweralkoxy, acetoxy, propionyloxy, butyryloxy, oenanthoyloxy, cypionoyloxy,trans-4-n-butyl-cyclohexanecarbonoyloxy, (C₂ -C₂₀) alkanoyloxy, loweralkoxy carbonyloxy, carboxy, (C₃ -C₂₀) alkenoyloxy, (C₃ -C₂₀)alkynoyloxy, (C₇ -C₁₀) aroyloxy or a divalent common species formedjointly by R₃.sbsb.(α) and R₃.sbsb.(β), said divalent commond speciesbeing selected from the group consisting of ═O, ═S, ═NR₃₆ or ═NOR₃₆wherein R₃₆ is hydrogen or lower alkyl;

wherein R₅ and R₁₀ are absent or selected from the group consisting ofhydrogen and lower alkyl;

wherein R₅ is selected from the group consisting of hydrogen, halogen,lower alkyl, amino and nitrile;

wherein R₇ is in α position and is hydrogen, hydroxyl, halogen, loweralkyl, lower alkoxy, lower alkylsilyl, amino, nitrile, nitro, nitroso,alkylsulfonyl, arylsulfonyl, lower alkylamino, dilower alkylamino, or isrepresented by the formula A¹ -[Y--A¹¹ ]_(u) --X--R₁₁, wherein:

u is an integer from 0 to 5; wherein A² and A¹¹ may be the same ordifferent and are selected from the group consisting of a bond,straight- or branched-chain alkylene, straight- or branched-chainalkynylene, straight- or branched-chain alkenylene, andfluoro-substituted analogs of the foregoing,

wherein A¹ and A¹¹ together have a total of from 3 to 30 carbon atoms,and Y is selected from the group consisting of --O--, --S--, --Se--,--SO--, --SO₂ --, --CO--, --NR₂₂ --, --SiR₂₂ R₂₂ --, --CR₂₂ OR₂₂ --,--NR₂₂ CO--, --NR₂₂ CS--, --CONR₂₂ --, --CSNR₂₂ --, --COO--, --COS--,--SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R₂₂ being hydrogen orlower alkyl); R₂₁ is selected from the group consisting of hydrogen,straight- or branched-chain lower alkyl, lower alkenyl or lower alkynyl,(C₃ -C₇) cycloalky, halogeno (lower) alkyl, halogeno (lower) alkyl,carboxy (lower) alkyl, (lower) alkoxycarbonyl (lower) alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁) arylalkyl, di(lower) alkylamino (lower) alkyl andfluorosubstituted analogs of the foregoing, and whrein X is --CONR₂₃ --,--CSNR₂₃ --, --NR₂₄ CO--, --NR₂₄ CS--, --NR₂₄ CONR₂₃ --, ##STR2## --SO₂NR₂₃ --, --CSS--, --SCS--, --NR₂₃ --, (NO)R₂₃ --, --(PO)R₂₃ --, --NR₂₄COO--, --NR₂₄ SO₂ --, --S--, --SO-- or --SO₂ --, (where R₂₃ is selectedfrom the group consisting of hydrogen, lower alkyl, and a species which,together with R₂₁, forms a saturated or unsaturated heterocyclic ringhaving at least one nitrogen atom and, aptionally, a second heteroatomselected from the group consisting of oxygen, sulfur, silicon, selenium,nitrogen and fluoro-substituted analogs of the foregoing, and where R₂₄is hydrogen or lower alkyl) wherein R₂₅ is hydrogen, nitrile or nitro)(XR₂₁ may form a tetrazole ring);

wherein R₁₁ is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, (C₅ -C₁₀) aryl, alkylsulfonyl,arylsulfonyl, a substituted 5-to-7 member heterocyclic ring having atleast one heteroatom (selected from oxygen, sulfur, silicon, selenium,nitrogen), --(CH₂)₅ W (wherein W is nitrile, hydroxyl, azido, nitroso,nitro, thionitrile, halogen, alkylsulfonyl or arylsulfonyl, and S is aninteger from 1 to 6), OR₂₆ (wherein R₂₆ is hydrogen, lower alkyl or (C₆-C₁₀) arly), DR₂₇ (wherein D is --Se--, --NR₂₆, --S-- or --O--, and R₂₇is hydrogen, lower alkyl), ═O, ═S, ═Se, ═NR₂₆ (wherein R₂₆ is hydrogenor lower alkyl;

wherein R₁₂ and R₁₃ are independently hydrogen or lower alkyl; whereinR₁₄ is selected from the group consisting of hydrogen, hydroxyl,nitrile, nitro, nitroso, halogen, lower alkyl, lower alkoxy, loweralkyseleno, lower alkylamino or diloweralkylamino; or R₁₄ and R₁₅together are --CH₃ --, --CHX--, --CX₃ --, (X=halogen, carboxyl oralkoxycarbonyl), --O--, --S--, --Se--, >N-CN, >NR₃₉ and >NCO₃ R₂₉wherein R₂₉ is hydrogen or lower alkyl;

wherein R₁₅ is selected from the group consisting of hydrogen, hydroxyl,nitro, nitroso, halogen, lower alkyl, lower alkenyl, lower alkynyl,lower alkoxy, lower alkylseleno, lower alkylamino, di(lower) alkylamino,nitrile, azido, arylseleno, AXR₂₁, A₁ -[Y-A¹¹ ]_(u) -X-R₂₁ or R₁₅ andR₁₆ together are --CH₂ --, --CHX--, --CX₂ --, (X=halogen, carboxyl oralkoxycarbonyl), --O--, --S--, --Se--, >N-CN, >NR₂₉ and >NCO₂ R₂₉wherein R₂₉ is hydrogen or lower alkyl;

wherein R₁₆ is selected from the group consisting of hydrogen, nitroso,halogen,lower alkyl, carboxyl, lower alkoxy, lower alkylseleno, loweralkylamino, nitrile, azido, arylseleno, lower alkylseleno, di(lower)alkylamino, AXR₂₁, or A¹ -[Y-A¹¹ ]_(u) -X-R₂₁,

R₁₅.sbsb.(α) and R₁₆.sbsb.(β) together are ═CG₂, where G is hydrogen,halogen, lower alkyl, lower alkenyl, lower alkynyl, nitrile,alkoxycarbonyl, alkylcarbonyl and carboxyl);

wherein R₁₇.sbsb.(α) is selected from the group consisting of hydrogen,hydroxyl, lower alkyl halogeno (lower)alkyl, AXR₂, A¹ -[Y-A¹¹ ]_(u)X-R₂₁, B¹ -T-R₃₀

wherein:

B¹ is straight- or branched-chain (C₁ -C₁₂) alkylene, (C₂ -C₁₂)alkynylene, (C₂ -C₁₂) alkynylene, (C₂ -C₁₂) alkenylene; T is --O--,--NR₃₁, --Se--, --S-- or S--S and R₃₀ and R₃₁ are inependently hydrogen,lower alkyl, or R₃₀ and R₃₁, together are (C₃ -C₇) cycloalkyl, (C₅ -C₇)cycloalkenyl, (C₃ -C₇) cycloalkyl or (C₅ -C₇) cycloalkenyl having one ormore hydrogen atoms replaced by halogen atoms, --HC═CHR₃₂ and --C═CR₃₃

wherein:

R₃₂ and R₃₃ are independently hydrogen, halogen, tri(lower) alkylsily,carboxyl, carbonyl, lower alkoxy, nitrile, sulfinyl lower alkyl, AXR₂₁,A¹ -[Y-A¹¹ ]_(u) -X-R₂₁ or a species represented by the formula:##STR3## wherein n and m are independently 0 to 6 and Q is --Se--,--SiH₂ --, --S--, --O-- --or NR₃₄ -- wherein R₃₄ is hydrogen, loweralkyl or (C₁ -C₇) alkanoyl;

or a species represented by the formula: ##STR4## wherein q is --CH₂ --,--S--, --O-- or --NR₃₅ -wherein R₃₅ is hydrogen or lower alkyl;

wherein R₁₇.sbsb.(β) is preferably selected from the group consisting ofhydrogen, hydroxyl, halogen, 1-oxo-2-propynyl, 1-hydroxy-2-propynyl,alkoxy, (C₁ -C₇) alkanoyloyloxy, (C₃ -C₇) alkenoyloxy, (C₃ -C₇)alkynoyloxy, alkenyloxy, cycloalkenyloxy, 1-alkyloxy-alkyloxy,1-alkyloxy cycloalkyloxy, alkylsilyloxy and a divalent common speciesformed jointly by R₁₇.sbsb.(α) and R₁₇.sbsb.(β), said divalent commonspecies being selected from the group consisting of ═O, ═S, ═NR₃₆ or═NOR₃₆ wherein R₃₆ is hydrogen or lower alkyl.

The invention further provides a method for inhibiting sex steroidformation in a warm-blooded animal, including man, by administering atherapeutically effective amount of a compound of the formula: ##STR5##

As used herein, the terms R₄₁, R₄₂, . . . , R₅₂ refer to substituentswhose locations on the phenylethyl frame work is illustrated in formulaII where the dotted lines represent an optional double bond of Z or Econfiguration. Unless specifically designated to the contrary, thecarbon bearing substituents may have either R or S stereochemistry. Insome embodiements, the optional double bonds are not present. When theoptional double bond are not present, R₄₆ and R₄₇ may each represent twoindependently-selected substituents. In certain preferred embodiment, asalt of the specified compounds may be used. Molecular structures setforth herein may be substituted or unsubstituted at any position wheresubstituents are not specifically defined. Those carbon atoms havingsubstituents defined may optionally be further substituted by a secondsubstituent; wherein E is absent, methylene or ethylene. wherein R₄₁,R₄₅, R₄₆, and R₅₃ are independently selected from the group consistingof hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, alkylsulfonyllower alkoxy, arylsulfonyl lower alkoxy, lower alkylsilyl, amino, nitro,nitrile and nitroso. wherein R₄₃, R₄₄, R₄₉ and R₅₁ are independentlyselected from the group consisting of hydrogen, hydroxyl, halogen, loweralkyl, lower alkoxy, alkylsulfonly lower alkoxy, arylsulfonyl loweralkoxy, lower alkylsilyl, amino, nitrile, nitro, nitroso, axido, loweralkylamino, dilower alkylamino, AXR₂₁, Y₄₇ -A¹ [Y-A¹ ]_(u) -X-R₂₁, A¹-[Y-A¹¹ ]_(u) --X--R₂₁ wherein:

A is straight- or branched-chain (C₁ -C₁₀) alkylene, (C₂ -C₁₀)alkenylene, (C₂ -C₃₀) alkynylene or fluoro-substituted analogs of theforegoing; u is an integer from 0 to 5; wherein A¹ and A¹¹ may be thesame or different and are selected from the group consisting of a bond,straigh- or branched-chain alkylene, straight- or branched-chainalkynylene, straight- or branched-chain alkenylene, andfluoro-substituted analogs of the foregoing, wherein A¹ and A¹¹ togetherhave a total of from 3 to 30 carbon atoms, and Y is selected from thegroup consisting of --O--, --S--, --Se--, --SO--, --SO₂ --, --CO--,--NR₂₂ --, --SiR₂₂ R₂₂ --, --CR₂₂ OR₂₂ --, --NR₂₂ CO--, --NR₂₂ CS--,--CONR₂₂ --, --CSNR₂₂ --, --COO--, --COS--, --SCO--, --CSS--, --SCS--,--OCO-- and phenylene (R₂₂ being hydrogen or lower alkyl); R₂₁ isselected from the group consisting of hydrogen, straight- orbranched-chain lower alkyl, lower alkenyl or lower alkynyl, (C₃ -C₇)cycloalkyl, halogeno (lower) alkyl, carboxy (lower) alkyl, (lower)alkoxycarbonyl (lower) alkyl, (C₅ -C₁₀) aryl, (C₇ -C₁₁) arylalkyl,di(lower) alkylamino (lower) alkyl and fluoro-substituted analogs of theforegoing, and wherein X is --CONR₂₃ --, --CSNR₂₃ --, --NR₂₄ CO--,--NR₂₄ CS--, --NR₂₄ CONR₂₃ --, ##STR6## --SO₂ NR₂₃ --, --CSS--, --SCS--,--NR₂₃ --, (NO)R₂₁ --, --(PO)R₂₃ --, --NR₂₄ COOO--, --NR₂₄ SO₂ --,--S--, --SC-- or --SO₂ --, (where R₂₃ is selected from the groupconsisting of hydrogen, lower alkyl, and a species which, together withR₂₁, forms a saturated or unsturated heterocyclic ring having at leastone nitrogen atom and, optionally, a second heteroatom selected from thegroup consisting of oxygen, sulfur, silicon, selenium, nitrogen andfluoro-substituted analogs of the foregoing, and where R₂₄ is hydrogenor lower alkyl) wherein R₂₅ is hydrogen, nitrile or nitro) (XR₂₁ mayform a tetrazole ring);

wherein R₄₃ and R₅₀ are independently selected from the group consistingof hydrogen, hydroxyl, halogen, lower alkyl, methoxy, ethoxy, propoxy,hydroxyethoxy, lower alkoxy, lower alkoxy carbonyloxy, carboxyl, acetoxypropionyloxy, butyryloxy, oenanthoyloxy, cypionyloxy,trans-4-n-butyl-cyclohexanecarbonoyloxy, (C₁ -C₂₀) alkanoyloxy, (C₃-C₂₀) alkenoyloxy, (C₃ -C₂₀) alkynoyloxy, (C₇ -C₁₁) aroyloxy andalkylsilyloxy;

wherein R₄₆ and R₄₇ are independently selected from the group consistingof hydrogen, amino, lower alkylamino, dilower alkyl amino, nitro,nitrile, nitroso, halogen, lower alkyl, lower alkenyl, lower alkynyl,halogeno lower alkyl, halogeno loweralkenyl, halogeno lower alkynyl,alkyl sulfonyl, aryl sulfonyl, a substituted 5-to-7 member heterocyclicring having at least one heteroatom (selected from oxygen, sulfur,silicon, selenium, nitrogen), --(CH₂)_(s) V (wherein V is nitrile,hydroxyl, azido, nitroso, alkoxy, nitro, thionitrile, halogen, alkylsulfonyl or aryl sulfonyl and s is an integer from 1 to 6), a moiety ofthe formula: ##STR7## wherein: F is absent or selected from the groupconsisting of alkyl, carbonyl or carboyxl, wherein the phenyl ring maybe halogenated, wherein R₅₁ is selected from the group consisting ofhydrogen, hydroxyl, halogen, lower alkenyl, lower alkynyl, nitrile,nitro, nitroso or X₄₆ (CH₂)_(n) Y₄₆ (X₄₆ being selected from the groupconsisting of --O--, --S--, --Sa--, --SO--, --SO₂ -- and --CO--, and Y₄₆being from the group consisting of hydroxyl, amino, monoalkyl amino,dialkyl amino, dimethyl N-oxide, N-aziridyl, guanidino, N-pyrrolidino,N-piperidino, N-methylpiperazino, N-morpholino and alkoxy, and n beingan integer from 1 to 6).

AXR₂₁, Y₄₇ -A¹ -[Y-A¹¹ ]_(u) --X--R₂₁ wherein A, A¹, A¹¹, X, Y, Y₄₇ aredefined previously for R₄₂, R₄₄, R₄₉ and R₅₁

R₄₆ and R₄₇ may also be a species which in combination with anothersubstituent from formula III, forms a moiety selected from the groupconsisting of --CH₂ --, --CHX--, --CX₂ -- (X being halogen, carboxyl oralkoxycarbonyl), --O--, --S--, --Se--, >N-CN, >NR₂₉ and >NCO₂ R₂₉ (R₂₉being hydrogen or lower alkyl), lower alkylene, --(CH₂)_(r) O(CH₂)_(s)--, --(CH₂)_(s) --, --(CH₂)_(r) Se(CH₂)_(s) --, --(CH₂)_(r) SO(CH₂)_(r)SO(CH₂)_(s) --, --(CH₂)_(r) SO₂ (CH₂)_(s) --, --(CH₂)_(r) CO(CH₂)_(s)--, --(CH₂)_(r) NR₂₂ (CH₂)_(s) --, --(CH₂)_(r) SiR₂₂ R₂₂ (CH₂)_(s) --and --(CH)₂.sbsb.r CR₂₂ OR₂₂ (CH₂)₂ _(s) -- (wherein R₂₂ being hydrogenor lower alkyl, r and s being independent integers from 0 to 3), amoisty of the formula: ##STR8## whrein: Z is absent or is selected fromthe group consisting of lower alkylene, halogeno lower alkylene,--(CH₂)_(n) O--, --(CH₂)_(n) S--, --(CH₂)_(n) Se--, --(CH₂)_(n) SO--,--(CH₂)_(n) SO₂ --, --(CH₂)_(n) CO--, --(CH₂)_(n) NR₂₂ --, --(CH₂)_(n)SiR₂₂ R₂₂ -- and --(CH₂)_(n) CR₂₂ OR₂₂ --, n eing an integer from 3, andR₇₁ being selected from a group consisting of hydrogen, hydroxyl,halogen, lower alkyl, lower alkoxy and lower alkylsil;

the formula:

    >N--A.sup.1 [Y-A.sup.11 ].sub.u --X--R.sub.11

wherein:

N is nitrogen atom and A¹, Y, A¹¹, u, X and R₂₁ are defined as above.

The invention further provides a method for inhibiting sex steroidformation in a warm-blooded animal, including man, by administering atherepeutically effective amount of a compound of the formula: ##STR9##

wherein the dotted lines represent optional double bonds; wherein E isabsent, methylene or ethylens; wherein R₄₃ is selected from the groupconsisting of hydrogen, alkyl, acetyl, propionyl, butyryl, oenanthoyl,cypionoyl, trans-4-n-butylcyclohexanecarbonoyl, (C₁ -C₂₀) alkanoyl, (C₃-C₂₀) alkenoyl, (C₃ -C₂₀) alkynoyl and (C₇ -C₁₁) aroyl; wherein R₄₆ isselected from the group consisting of hydrogen, halogen, amino, lowermono- or dialkylamino, nitro, nitrile, nitroso, lower alkyl, loweralkenyl, lower alkynyl, halogeno analogs of the foregoing; a substituted5- to 7-member heterocyclic ring having at least one heteroatom(selected from oxygen, sulfur, silicon, selenium, nitrogen) --(CH₂)_(s)V (wherein V is nitrile, hydroxyl, azido, nitroso, alkoxy,nitro,thionitrile, halogen, alkyl sulfonyl, aryl sulfonyl and s is an integerfrom 1 to 6) and the formula: ##STR10## wherein: F is absent or selectedfrom the group consisting of alkyl, carbonyl and carbonyl; wherein thephenyl ring may be halogenated, wherein R₆₁ is selected form the groupconsisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkenyl,lower alkynyl, nitrile, nitro and nitroso

wherein R₄₅ and R₅₄ are independently selected from the group consistingof hydrogen and lower alkyl or R₄₅ and R₅₄ together from a moietyselected from the group consisting of (CH₂)_(n) (n being an integer from0 to 3), CHX, CX₂ (X being halogen, carboxyl or alkoxycarbonyl),--CH═CH--, --O--, --S--, --Se--, >N--CN, >NR₂₉ (R₂₉ being hydrogen orlower alkyl), --(CH₂ O)--, --(CH₂ S)--, --(CH₃ Se)--, --CH₂ SO)--,--(CH₂ SO₂)-- and --(CH₂ CO)--; wherein substituents R₄₉, R₅₀ and R₅₁are independently selected from the group consisting of hydrogen,hydroxyl, (C₁ -C₂₀)alkanoyloxy, (C₃ -C₂₀)alkenoyloxy, (C₃-C₂₀)alkynoyloxy and (C₇ -C₁₁)aroyloxy; wherein R₅₂ is hydrogen or loweralkyl; wherein u is an integer from 0 to 5; wherein A¹ and A¹¹ may bethe same or different and are selected from the group consisting of abond, straight- or branched-chain alkylene, straight- or branched-chainalkynylene, straight- or branched-chain alkenylene andfluoro-substituted analogs of the foregoing, wherein A¹ and A¹¹ togetherhave a total of from 3 to 30 carbon atoms, and Y is selected from thegroup consisting of --O--, --S--, --Se--, --SO--, --SO₂ --, --CO--,--NR₂₂ --, --SiR₂₂ R₂₂ --, --CR₂₂ OR₂₂ --, --NR₂₂ CO--, --NR₂₂ CS--,--CONR₂₂ --, --CSNR₂₂ --, --COO--, --COS--, --SCO--, --CSS--, --SCS--,--OCO-- and phenylene (R₃₃ being hydrogen or lower alkyl); R₂₁ isselected from the group consisting of hydrogen, straight- orbranched-chain lower alkyl, lower alkenyl or lower alkynyl, (C₃-C₇)cycloalkyl, halogeno(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl and fluoro-substituted analogs of theforegoing, and wherein X is --CONR₂₃ --, --CSNR₂₃ --, --NR₂₄ CO--,--NR₂₄ CS--, --NR₂₄ CONR₂₃ 13 , ##STR11## --SO₃ N₂₃ --, --CSS--,--SCS--, --NR₂₃ --, --(NO)R₂₃ --, --(PO)R₂₃ --, --NR₂₄ COO--, --NR₂₄ SO₂--, --S--, or --SO₂ --, (where R₂₃ is selected from the group consistingof hydrogen, lower alkyl, and a species which, together with R₂₁, formsa saturated or unsaturated heterocyclic ring having at least onenitrogen atom and, optionally, a second heteroatom selected from thegroup consisting of oxygen, sulfur, silicon, selenium, nitrogen andfluoro-substituted analogs of the foregoing, and where R₂₄ is hydrogenor lower alkyl) wherein R₂₅ is hydrogen, nitrile or nitro) (XR₂₁ mayform a tetrazole ring).

The compounds shown above may inhibit androgen and estrogen biosynthesisinter alia through inhibition of sex steroid biosynthesis enzymes,including, but not limited to 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Many of the inhibitors disclosed herein also act as sexsteroid antagonists which are therefore able both to inhibit sex steroidformation and to act as antagonists to sex steroid activity by blockingsex steroid receptors. For example, preferred antiestrogens which alsoact as inhibitors of estrogen formation include, but are not limted to,N-butyl, N-methyl-11-(16α-chloro-3',17'β-dihydroxyestra-1',3',5'(10')-trien-7'α-yl) undecanamide ("EM 139"),17β-hydroxy-17α(12'-iodododecynyl)-Δ⁴ -androsten-3-one ("EM 150"),N-butyl,N-methyl-11-(3'-hydroxy-16'-methylen-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)undecanamide ("EM 175"), N-butyl,N-methyl-11-(3',17'β-dihydroxy-16'-methylenestra-1',3',5'(10')-trien-7'α-yl) undecanamide ("EM 186"), N-butyl,N-methyl-11-(3',17'β-dihydroxy-19'-nor-(17'α)pregn-1',3',5'(10')-20'-yn-7α-yl) undecanamide ("EM 104"). Sex steroidinhibitor progesties of the compounds of the present invention,especially the blockade of androgen and estrogen formation, may play acrucial role in the therapeutic efficacy of the compounds whenadministered for the treatment of estrogen- as well asandrogen-sensitive diseases. Such diseases include, but are not limitedto, malignant as well as non-malignant steroid-sensitive diseases,especially brease cancer, prostate cancer, ovarian cancer, endometrialcancer, endometriosis, uterine leiomyomata, precocious puberty,hirsutism, acne, seborrhea, androgenic alopecia, benign prostatichyperplasia, sexual deviants as well as for male and femalecontraception. These newly discovered properties permit a blockade at astep preceeding steroid receptors, thus acting prior to and in additionto the action of steroid antagonists (e.g. antiestrogens orantiandrogens).

The invention further provides novel inhibitors of sex steroidformation. Preferred inhibitors include the compounds of general formulaI set forth below. Especially preferred are those compounds of generalformula I wherein R₁₆(β) is chlorine, bromine, fluorine or iodine, orwherein R₁₄(α) and R₁₆(β) togehter form ═CG₂ (G being hydrogen, halogenlower alkyl, lower alkenyl, lower aklynyl, nitrile, alkoxycarbonyl,alkycarbonyl or carboxyl).

According to the invention, the above-indicated activities arepreferably obtained inter alia with a steroid derivatives of the generalformula I: ##STR12##

As used herein, the terms R₁, R₂, . . . , R₁₇ refer to substituentswhose locations on the steroid nucleus are illustrated in the formula I,wherein the dotted lines represent optional double bonds and wherein theA-ring is optionally aromatic. Unless specifically designated to thecontrary, substituents may have either α or β stereochemistry, or an Rgroup may represent two substituents, one in an α position and the otherin β position.

The optional double bonds are independent from each other. In someembodiments, no double bonds are present. When appropriate, a salt ofthe estradiol derivatives may be used. Carbon atoms of the steroidalnucleus whose substituents are not expressly defined in a structuralformula may optionally be substituted or unsubstituted. Those carbonatoms having a defined substituent may optionally be further substitutedby a second substituent. As used herein, the term "lower", whendescribing a carbon-containing moiety, means a moiety having 8 or fewercarbon atoms. For instance, a "lower alkyl" means a C₁ to C₈ alkyl.

Certain preferred substituents of steroid derivatives in accordance withthe invention include, but are not limited to, the following:

R₁, R₂ and R₄ are preferably independently selected from the groupconsisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy,alkylsulfonyl lower alkoxy, arylsulfonyl lower aloxy, lower alkylsilyl,amino and nitro;

R₃ is preferably selected from the group consisting of hydroxyl,halogen, lower alkyl, lower alkoxy (such as methoxy, ethoxy, propoxy orhydroxyethoxy), lower alkoxy carbonyloxy, carboxy, (C₁ -C₂₀)alkanoyloxy(such as acetate, propionate, butyrate, hemisuccinate, oenanthate,cypionate or cyclohexanecarboxylate), (C₃ -C₂₀)alkenoyloxy, (C₃-C₂₀)alkynoyloxy, (C₇ -C₁₀)aroyloxy (such as benzoate) and a divalentcommon species formed jointly by R₃ (α) and R₃ (β), said divalent commonspecies being selected from the group consisting of ═O, ═S, ═NR₃₆ or═NOR₃₅ wherein R₃₆ is hydrogen or lower alkyl;

R₅ and R₁₀ are absent or preferably selected from the group consistingof hydrogen or lower alkyl;

R₅ is preferably selected from the group consisting of hydrogen,hydroxyl, halogen, lower alkyl, amino and nitrile;

R₇ is preferably in the α position and is preferably selected from thegroup consisting of hydrogen, hydroxyl, halogen, lower alkyl, loweralkoxy, lower alkylsilyl, amino, nitro, nitroso, nitrile, alkylsulfonyl, aryl sulfonyl, lower alkylamino, diloweralkylamino, AXR₂₁ andA¹ -[Y-A¹¹ ]_(u) -X-R₂₁ wherein;

A is straight- or branched-chain (C₁ -C₃₀)alkylene, (C₂ -C₃₀)alkenylene,(C₂ -C₃₀)alkynylene, fluoro-substituted analogs of the foregoing,wherein u is an integer from 0 to 5, wherein A² and A¹¹ may be the sameor different and are selected from the group consisting of a bond,straight- or branched- branched-chain alkylene, straight- orbranched-chain alkynylene, straight- or branched-chain alkenylene, andfluoro-substituted analogs of the foregoing, wherein A¹ and A¹¹ togetherhave a total of from 3 to 30 carbon atoms, and Y is selected from thegroup consisting of --O--, --S--, --Se--, --SO--, --SO₂ --, --CO--,--NR₂₂ --, --SiR₂₂ R₂₂ --, --CR₂₂ OR₂₂ --, --NR₂₂ CO--, --NR₂₂ CS--,--CONR₂₂ --, --CSNR₂₂ --, --COO--, --COS--, --SCO--, --CSS--, --SCS--,--OCO-- and phenylene; (where R₂₂ is hydrogen or lower alkyl), whereinR₂₁ is selected from the group consisting of hydrogen, straight- orbranched-chain lower alkyl, lower alkenyl or lower alkynyl, (C₃-C₇)cycloalkyl, halogeno(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl and fluorosubstituted analogs of theforegoing, and wherein X is --CONR₂₃ --, --CSNR₂₃ --, --NR₂₄ CO--,--NR₂₄ CS--, --NR₂₄ CONR₂₃ 13 , ##STR13## --SO₂ NR₂₃ --, --CSS--,--SCS--, --NR₂₃ --, --(NO)R₂₃ --, --(PO)R₂₃ --, --NR₂₄ COO--, --NR₂₄ SO₂--, --S--, or --SO₂ --, (where R₂₃ is selected from the group consistingof hydrogen, lower alkyl, and a species which, together with R₂₁, formsa saturated or unsaturated heterocyclic ring having at least onenitrogen atom and, optionally, a second heteroatom selected from thegroup consisting of oxygen, sulfur, silicon, selenium, nitrogen andfluoro-substituted analogs of the foregoing, and where R₂₄ is hydrogenor lower alkyl); wherein R₂₅ is hydrogen, nitrile or nitro; XR₂₁ mayform a tetrazole ring in certain embodiments;

R₁₁ is preferably selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, (C₆ -C₁₀)aryl, alkyl sulfonyl, arylsulfonyl, a substituted 5- or 7-member heterocyclic ring having at leastone hetero atom (selected from oxygen, sulfur, silicon, selenium,nitrogen), --(CH₂)_(s) W (wherein W is nitrile, hydroxyl, azido,nitroso, nitro, thionitrile, halogen, alkyl sulfonyl, aryl sulfonyl ands is an integer from 1 to 6), OR₂₆ (wherein R₂₅ is hydrogen, lower alkylor (C₅ -C₁₀)aryl), DR₂₇ (wherein D is --Se--, --NR₂₅ --, --S-- or --O--,and R₂₇ is hydrogen or lower alkyl), ═O, ═S, ═Se, ═NR₂₈ and ═NOR₂₈(wherein R₂₈ is hydrogen or lower alkyl);

R₁₂ and R₁₃ are preferably independently hydrogen or lower alkyl;

R₁₄ is preferably selected from the group consisting of hydrogen,hydroxyl, nitrile, nitro, nitroso, halogen, lower alkyl, lower alkoxy,lower alkylsulfonyl, lower alkylseleno, lower alkylamino anddiloweralkylamino, or R₁₄ and R₁₅ together are --CH₂ --, --CHX--, --CX₂-- (where X is halogen, carboxyl or alkoxycarbonyl), --O--, --S--,--Se--, >N--CN, >NR₂₉ or >NCOR₂₉ (where R₂₉ is hydrogen or loweralkyl);

R₁₅ and R₁₆ are preferably independently selected from the groupconsisting of hydrogen, hydroxyl, nitro, nitroso, halogen, lower alkyl,lower alkenyl, lower alkynyl, lower alkoxy, lower alkylseleno, loweralkylamino, di(lower)alkylamino, nitrile, azido, arylseleno, alkylsulfonyl, aryl sulfonyl, AXR₂₁, A¹ -[Y--A²² ]_(u) --X-R₂₁, or R₁₆ (α)and R₁₅ (β) together are ═CG₂ (where G is hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl, nitrole, alkoxycarbonyl,alkylcarbonyl and carboxyl), or R₁₅ and R₁₆ together are --CH₂ --,--CHI--, --CI₂ --, (where I is halogen, carboxyl or alkoxycarbonyl),--O--, --S--, --Se--, >N--CN, >NR₂₉ and >NCO₂ R₂₉ (where R₂₉ is hydrogenor lower alkyl);

R₁₇(α) is preferably selected from the group consisting of hydrogen,hydroxyl, lower alkyl, halogeno(lower)alkyl, AXR₂₁, A¹ -[Y--A¹¹ ]_(u)--X--R₂₁, B¹ --T--R₃₀ (where B¹ is straight- or branched-chain (C₁-C₁₂)alkylene, (C₂ -C₁₂)alkylene, (C₃ -C₁₂)alkynylene, or (C₂-C₁₂)alkenylene, where T is --O--, --NR₃₁ --, --Se--, --S-- or S--S andR₃₀ and R₃₁ are independently hydrogen or lower alkyl, or R₃₀ and R₃₁together are (C₃ -C₇)cycloalkyl, (C₅ -C₇)cycloalkenyl, (C₃-C₇)cycloalkyl or (C₅ -C₇)cycloalkenyl (said cycloalkenyl having one ormore hydrogen atoms replaced by halogen atoms). --HC═CHR₃₂ and--C.tbd.CR₃₃ wherein R₃₂ and R₃₃ are independently hydrogen, halogen,tri(loweralkyl)silyl, carboxyl, carbonyl lower alkoxy, nitrile, sulfinyllower alkyl, (C₂ -C₁₀)alkyl, (C₁ -C₂₀)halo alkyl, AXR₂₁, A¹ -[Y--A¹¹]_(u) --X--R₂₁, a species represented by the formula ##STR14## wherein nand m are independent intergers from 0 to 6 and Q is --Se--, --SiH₂ --,--S--, --O-- or --NR₃₄ -- (wherein R₃₄ is hydrogen, lower alkyl or (C₁-C₇)alkanoyl), a species represented by the formula ##STR15## where q is--CH₂ --, --S--, --O-- or --NR₃₅ (R₃₅ being hydrogen or lower alkyl);

R₁₇(β) is preferably selected from the group consisting of hydrogen,hydroxyl, halogen, 1-oxo-2-propynyl, 1-hydroxy-2-propynyl, (C₁-C₇)alkanoyloxy (such as acetate, propionate, butyrate, hemisuccinate,oenanthate, cypionate or cyclohexanecarboxylate, (C₃ -C₇)alkenoyloxy,(C₃ -C₇)alkynoyloxy, alkylcarbonyl, alkenyloxy, cycloalkenyloxy,1-alkyloxy-alkyloxy, 1-alkyloxy cycloalkyloxy, alkylsilyloxy and adivalent common species formed jointly by R₁₇(α) and R₁₇(β), saiddivalent common species being selected from the group consisting of ═O,═S, ═NR₃₆ or ═NOR₃₆ wherein R₃₆ is hydrogen or lower alkyl.

In certain preferred embodiments, R₁₇(α) is hydroxyl. In other preferredembodiments, at least one substituent selected from the group consistingof R₇(α), R₁₅, R₁₆ and R₁₇(α) is A¹ -[Y--A¹¹ ]_(u) --X--R₂₁.

A useful non-steroidal inhibitor has general formula IV: ##STR16## wherethe dotted lines represent an optional double bond of Z or Econfiguration.

Certain preferred substituents include, but are not limited to thefollowing:

R₄₁, R₄₅, R₄₈, R₅₂ are preferably independently selected from the groupconsisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy,alkylsulfonyl lower alkoxy, arylsulfonyl lower alkoxy, lower alkylsilyl,amino, nitro, nitrile and nitroso.

R₄₃, R₄₄, R₄₉ and R₅₁ are preferably independently selected from thegroup consisting of hydrogen, hydroxyl, halogen, lower alkyl, loweralkoxy, alkylsulfonyl lower alkoxy, arylsulfonyl lower alkoxy, loweralkylsilyl, amino, nitrile, nitro, nitroso, azido, lower alkylamino,dilower alkylamino, AXR₂₁, Y₄₇ -A¹ [Y--A¹¹ ]_(u) --X--R₂₁, and A¹-[Y--A¹¹ ]_(u) --X--R₂₁ wherein A, A¹, A¹¹, X, Y and u are defined aspreviously in formula I and wherein Y₄₇ is absent or selected from thegroup consisting of carbonyl and carboxyl.

R₄₃ and R₅₀ are preferably independently selected from the groupconsisting of hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy(such as methoxy, ethoxy, propoxy or hydroxyethoxy), lower alkoxycarbonyloxy, carboxyl, (C₁ -C₂₀) alkanoyloxy (such as acetate,propionate, butyrate, hemisuccinate, oenanthate, cypionate orcyclohexanecarboxylate), (C₃ -C₂₀) alkenoyloxy, (C₃ -C₂₀) alkynoyloxy,(C₇ -C₁₁) aroyloxy and alkylsilyloxy.

R₄₆ and R₄₇ are preferably independently selected from the groupconsisting of hydrogen, amino, lower alkylamino, dilower alkyl amino,nitro, nitrile, nitroso, halogen, lower alkyl, lower alkenyl, loweralkynyl, halogeno lower alkyl, helogeno lower alkenyl, halogeno loweralkynyl, alkyl sulfonyl, aryl sulfonyl, a substituted 5- to 7-memberheterocyclic ring having at least one heteroatom (selected from oxygen,sulfur, silicon, selenium, nitrogen), --(CH₂)_(s) V (wherein V isnitrile, hydroxyl, azido, nitroso, alkoxy, nitro, thionitrile, halogen,alkyl sulfonyl or aryl sulfonyl and s is an integer from 1 to 6), amoiety of the formula: ##STR17## wherein: F is absent or selected fromthe group consisting of alkyl, carbonyl, or carboxyl, wherein the phenylring may be halogenated, wherein R₆₁ is hydrogen, hydroxyl, halogen,lower alkyl, lower alkenyl, lower alkynyl, nitrile, nitro, nitroso orX₄₅ (CH₂)_(n) Y₄₅ (X₄₆ being selected from the group consisting of--O--, --S--, --Se--, --SO--, --SO₂ -- and --CO--, and Y₄₅ beingselected from the group consisting of hydroxyl, amino, monoalkyl amino,dialkyl amino, dimethyl N-oxide, N-aziridyl, guanidino, N-pyrrolidino,N-piperidino, N-methylpiperazino, N-morpholino and alkoxy, and n beingan integer from 1 to 6, preferably 3);

AXR₂₁, Y₇ -A¹ -[Y-A¹¹ ]_(u) -X-R₂₁, and A¹ -[Y-A¹¹ ]_(u) -X-R₂₁,wherein, A, A¹, A¹¹, X, Y, Y₃₇ and u are defined as previously for R₄₂,R₄₄, R₄₉ and R₅₁.

R₄₅ and R₄₇ may also be a species which, in combination with anothersubstituent of general molecular formula III, form a moiety selectedfrom the group consisting of: --CH₂ --, CHX, CX₂ (X being halogen,carboxyl or alkoxycarbonyl), --O--, --S--, --Se--, >N--CN, >NR₂₉ and>NCO₂ R₂₉ (R₂₉ being hydrogen or lower alkyl), lower alkylene,--CH(CH₃)--, --CH═CH--, --(CH₂)_(r) O(CH₂)_(s) --, --(CH₂)_(r)S(CH₂)_(s) --, --(CH₂)_(r) Se(CH₂)_(s) --, --(CH₂)_(r) SO(CH₂)_(s) --,--(CH₂)_(r) SO₂ (CH₂)_(s) --, --(CH₂)_(r) CO(CH₂)_(s) --, --(CH₂)_(r)NR₂₂ (CH₂)_(s) --, --(CH₂)_(r) SiR₂₂ R₂₂ (CH₂)_(s) -- or --(CH₂)_(r)CR₂₂ OR₂₂ (CH₂)_(s) -- (wherein R₂₂ being hydrogen or lower alkyl, r ands being independent integers from 0 to 3), a moiety of the formula:##STR18## wherein: A¹, Y, A¹¹, u, X and R₂₁ are as defined above,wherein Z is absent or is selected from the group consisting of loweralkylene, halogeno lower alkylene, --(CH₂)_(n) O--, --(CH₂)_(n) S--,--(CH₂)_(n) Se--, --(CH₂)_(n) SO--, --(CH₂)_(n) SO₂ --, --(CH₂)_(n)CO--, --(CH₂)_(n) NR₃₃ --, --(CH₂)_(n) SiR₂₂ R₂₂ -- and --(CH₂)_(n) CR₂₂OR₂₂ --, R₂₂ as defined above, n being an integer from 0 to 3, and R₇₁being selected from a group consisting of hydrogen, hydroxyl, halogen,lower alkyl, lower alkoxy and lower alkylsilyl, a moiety of the formula:

    >N-A.sup.1 [Y-A.sup.11 ].sub.u -X-R.sub.21                 8

wherein N is nitrogen atom and A¹, A¹¹, u, Y, X and R₂₁ are as definedabove.

In preferred embodiments, moieties which are combinations of R groupsfrom general molecular structure IV, are combinations of R₄₆ and R₄₇,R₄₆ with R₄₁ or R₅₂, or R₄₇ with R₄₅ or R₄₈.

The foregoing compounds are potent inhibitors of sex steriod formation,especially 17β-hydroxysteroid dehydrogenase activity. This may bedemonstrated by inhibiting enzymatic activity in vitro using purifiedenzyme from human placenta (Thomas et al., J. Biol. Chem. 258,11500-11504, 1983). The antiestrogenic activity of the compounds ismeasured in vitro in estrogen-sensitive human breast cancer cellsZR-75-1 (Poulin et al., Cancer Res. 46, 4933-4937, 1986) while the invivo action is measured as the potency of the compound to reverse theestradiol-induced increase of uterine weight in adult ovariectomizedmice.

In particular, a preferred inhibitor produces antisteroid effects at adose possessing no agonistic activity, unlike compounds such asTamoxifen, which possesses some agonistic properties which limit theirtherapeutical efficiency (Wakeling and Bowler, J. Steroid Biochem. 30,141-147, 1988).

Such compounds administered at appropriate doses are of value in allconditions where antiestrogens and antiandrogens are beneficial. Inparticular, this approach is of value in breast cancer, prostate cancer,endometrial cancer, ovarian cancer, endometriosis, benign prostatichyperplasia, precocious puberty, hirsutism, acne, seborrhea, androgenicalopecia, menstrual disorders and as male and female contraceptive aswell as in sexual deviants.

When used to block 17β-hydroxysteroid dehydrogenase activity, and forantiandrogenic and antiestrogenic effects in warm-blooded animals, atypical daily dose is 0.1 to 25 mg/kg administered by injection ororally. In man, this is equivalent to an oral dose of 2.5 to 1250mg/day. The compounds are more conveniently administered to main in theform of a pharmaceutical composition.

When patients whose tests or ovaries, respectively, have already beensurgically removed are treated according to this invention, theadministration and dosage of the above-described compound (multi sexhormone blocker) are the same as in intact patients or patientsreceiving an LHRH agonist or antagonist.

The hormone blocker useful in the present invention is typicallycompounded in customary ways for oral administration, e.g., in capsules,tablets, as dragees or even in liquid form, e.g., suspensions or syrups.The active substance, with or without additional types of active agents,can be worked into tablets or dragee cores by being mixed with solid,pulverulent carrier substances, such as sodium citrate, calciumcarbonate or dicalcium phosphate, and binders such as polyvinylpyrrolidone, gelatin or cellulose derivatives, possibly by adding alsolubricants such as magnesium stearate, sodium lauryl sulfate, "Carbowax"or polyethylene glycols. Of course, tase-improving substances can beadded in the case of oral administration forms.

The therapeutically active hormone blocker should be present in aconcentration of about 0.5-90% by weight of the total mixture, i.e., inamounts that are sufficient for maintaining the above-mentioned dosagerange.

As further forms of administration, one can use plug capsules, e.g., ofhard gelatin, as well as closed soft-gelatin capsules comprising asoftener or plasticizer, e.g., glycerine. The plug capsules contain theactive substance preferably in the form of a granulate, e.g., in mixturewith fillers, such as lactose, saccharose, mannitol, starches, such aspotato starch or amylopectin, cellulose derivatives or highly-dispersedsilica acids. In soft-gelatin capsules, the active substance ispreferably dissolved or suspended in liquids, such as vegetable oils orliquid polyethylene glycols.

In place of oral administration, all the active compounds may beadministered parentally. In such case, one can use a solution of theactive substance, e.g., in sesame oil or olive oil.

The hormone blocker may also be microencapsulated in or attached to abiocompatable, biodegradable polymer, e.g.,poly(d,1-lactide-coglycolide) and subcutaneously or intramuscularlyinjected by a technique called subcutaneous or intramuscular depot toprovide continuous, slow release of the compound over a period of 15days or longer.

The composition may contain, in addition to the storoid and/ornonsteroidal derivatives of the invention, other antiestrogens and/orantiandrogens and/or enzymatic inhibitors and/or inhibitors of ACTHand/or growth hormone and/or prolactin secretion.

Set forth below, by way of example and not by way of limitation, aresome preferred techniques for synthesis of preferred inhibitors of sexsteroid formation in accordance with the invention. Those of skill inthe art will recognize conventional variations for producingmodifications or analogs of the various compounds shown in the syntheticpathways described below.

SYNTHESIS OF PREFERRED INHIBITORS

Instrumentation

IR spectra were obtained in a Perkin-Elmer spectrometer 1310. UV spectrawere recorded in methanol on a Beckman DU-6 spectrometer. H-NMR spectrawere obtained at 200 MHz on a Varian XL-200 spectrometer. Chemicalshifts are reported in ppm units with tetramethylsilane as internalstandard. Mass spectra were obtained on Micromass 16F spectrometer.

EXAMPLE 1

Synthesis of the N-butyl,N-methyl-11-(3',17'β-dihydroxy-16'-methylenestar-1',3',5'(10')-trien-7'-α-yl)undecanamide ("EM 186") (The synthesis of this compound is described inthe scheme I where n=10)

N-butyl,N-methyl-11-(3'-hydroxy-16'-methylen-17'-oxo-estra-1',3',5'(10')trien-7'α-yl) undecanamide ("EM 175")

A mixture of N-butyl,N-methyl-11-(3',17'β-dihydroxy-estra-1',3',5'-(10')-trien-7α-yl)undecanamide (1) (427 mg, 1 mM), paraformaldehyde (150 mg, 5 mM), drydimethylamine hydrochloride (466 mg, 7 mM) isoamyl alcohol (10 ml) isrefluxed for 2 hours. After concentration under reduced pressure, thereaction mixture is poured in dilute hydrochloric acid (1:9, 50 cc),washed with ether (X3), alkalinized by adding a saturated solution ofsodium carbonate and extracted (3X) with chloroform. The chloroformlayers are washed with water and concentrated to dryness. Water is addedto the resulting oil and the mixture is subjected to steam distillationuntil the distillate is neutral. The residue is cooled and subjected to"flash chromatography" on silica gel (Kieselgel 60, Merck, 250 meshASTM). The elution performed with a mixture of hexane, ethyl acetate(7:3 v/v) gives the N-butyl,N-methyl-11-(3'-hydroxy-16'-methylen-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)undecanamide ("EM 175").

N-butyl,N-methyl-11-(3',17'β-dihydroxy-16'-methylen-estra-1',3',5'(10')-trien-7'α-yl)undecanemaide ("EM 186")

N-butyl,N-methyl-11-(3'-hydroxy-16'-methylen-17'-oxo-estra-1',3',5'(10')-trien-7'.alpha.-yl)undecaneamide ("EM 175") (400 mg) obtained above is dissolved in 10 mlof methanol and mixed with a solution of 200 mg of sodium borohydride in10 ml of water. After stirring for three hours at room temperature, adrop of acetic acid is added. The mixture poured in saturated sodiumchloride solution is extracted with ethyl acetate (3X). The organiclayers are washed with water, dried on anhydrous MgSO₄ and evaporated todryness under reduced pressure. The residue is chromatographed on silicagel (Kieselgel, 60F254, Merck, 0.063, 0.200 mm, 20 g). Elution with amixture of hexane-ethyl acetate (6:4 v/v) gives the N-butyl,N-methyl-11-(3',17'β-dihydroxy-16'-methylen-estra-1',3',5'(10')-trien-7α-yl)undecaneamide ("EM 186").

3'-benzoate of N-butyl,N-methyl-11-(3',17'β-dihydroxy-16'-methylen-estra-1',3',5'(10')-trien-7α-yl)undecanemaide

The 16-methylen-3,17β-alcohol ("EM 186") (45 mg, 0.1 mmol) obtainedpreviously is dissolved in acetone (1 ml) and a sodium hydroxidesolution (1N, 120 μl). The mixture is cooled to 0° C. and benzoylchloride (14 μl, 0.12 mmol) is added dropwise. The mixture is thenstirred for 40 minutes at 0° C. and then diluted with water. Thesolution is extracted with ethyl acetate (3X) and the organic layers arewashed with a saturated sodium bicarbonate solution and water. The ethylacetate solution is dried under vacuum. The residue is immediatelychromatographed on silica gel (Kieselgel, 60F254, 0.063-0.200 mm, 500g). Elution with hexane ethyl acetate (4:1 v/v) give the 3-benzoate ofN-butyl,N-methyl-11-(3',17'β-dihydroxy-16'-methylen-estra-1',3',5'(10')-trien-7'α-yl)undecaneamide.

By methods analogous to those described above and using the same orother corresponding starting materials and the same or correspondingacid chloride, the following synthesis are performed. One can thusprepare esters or other corresponding 2 to 20 carbon hydrocarboncarboxylic acid esters of N,N'dialkyl-11-(3',17'β-dihydroxy-16'-methylen-estra-1',3',5'(10')-trien-7α-yl)alkamides 2 as summarized in Table 1.

                  TABLE 1                                                         ______________________________________                                        N,N' dialkyl-11-(3',17'β-dihydroxy-16'-methylen-estra-1',3',5'(10')-     trien-7'α-yl) alkylamide                                                 ##STR19##                                                                    n    R               R.sub.1 R.sub.3                                          ______________________________________                                        10   H               methyl  n-butyl                                          10   H               H       n-butyl                                          10   H               methyl  1H, 1H-heptafluorobutyl                          10   H               methyl  n-pentyl                                         10   C.sub.6 H.sub.5 CO                                                                            methyl  n-butyl                                          10   CH.sub.3 CO     methyl  n-butyl                                          10   C.sub.3 H.sub.5 CO                                                                            methyl  n-butyl                                          10   C.sub.6 H.sub.23 CO                                                                           methyl  n-butyl                                          10   Cyclo C.sub.5 H.sub.9 (CH.sub.3)CO                                                            methyl  n-butyl                                          10   C.sub.6 H.sub.11 CO                                                                           methyl  n-butyl                                          10   CH.sub.3 (CH.sub.2).sub.16 CO                                                                 methyl  n-butyl                                           9   H               methyl  n-butyl                                           9   C.sub.6 H.sub.5 CO                                                                            methyl  n-butyl                                           9   C.sub.3 H.sub.7 CO                                                                            methyl  n-butyl                                           8   H               methyl  n-butyl                                           8   C.sub.6 H.sub.3 CO                                                                            methyl  n-butyl                                          ______________________________________                                         ##STR20##

EXAMPLE 2

Synthesis of N-butyl,N-methyl-11-(16α-chloro-3',17'β-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 139", Scheme 2)

N-butyl, N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10'),16'-tetraen-7'α-yl) undecanamide (5)

To 11-(3-benzoyloxy-17-oxo-estra-1,3,5(10)-trien-7α-yl) undecanoic acid(3) (3.94 g, 7.22 mmol) (prepared as described in Bucourt et al., J.Biol. Chem. 253: 8221-8228, 1978, which is hereby incorporated herein byreference), dissolved in anhydrous CH₂ Cl₃ (100 ml) and cooled at -10°C. was added tributylamine (2.18 ml, 9.15 mmol) andisobutylchloroformate (1.30 ml. 10.0 mmol). The solution was stirredduring 35 min. and N-methylbutylamine (13 ml, 109.7 mmol) was added. Themixture was warmed to room temperature and stirred during 1 h.Afterward, CH₂ Cl₂ was added and the organic phase was washed with 1NHCl, water saturated sodium bicarbonate solution and finally with water,dried with anhydrous MgSO₄ and the solvent was removed under reducedpressure. The residue was purified by chromatography on silica gel.Elution with mixture of EtOAc/hexane (1.5:8.5 v/v) yielded N-butyl,N-methyl-11-(3'-benzoyloxy-17'-oxo-estra- 1',3'5'(10')-trien-7'α-yl)undecanamide (4.25 g, 96%) as colorless oil; IR ν (neat) 1750, 1725 and1640 cm⁻¹. The above described benzoyloxy amide (341 mg, 0.54 mmol) wasdissolved in methanol (10 ml) and cooled at 0° C. Following this 2N NaOH(5 ml) was added and the mixture was stirred during 60 min. at 0° C. Thesolution was neutralized with 1N HCl and extracted with CH₂ Cl₂. Theorganic phase was dried with anhydrous MgSO₄ and the solvent was removedunder reduced pressure. The residue was purified by chromatography onsilica gel. Elution with mixture of EtOAc/hexane (3:7 v/v) yieldedN-butyl,N-methyl-11-(3'-hydroxy-17'-oxo-estra-1',3',4'(10')-trien-7'α-yl)undecanamide (4) 284 mg, 97%) as colorless oil; ¹ H-NMR δ (CDCl₃) 0.91(s, 3H,18'-CH₂), 2.76_(app) (d,1HJ=16.3 Hz, part of ABX system 6'-H)2.96 and 2.98 (2s,3H N-CH₃), 3.27 and 3.38 (2t_(app),2H,J=7.5 Hz,N-CH₂--), 6.63 (broad s,1H,4'-H), 6.70 (broad d,1H,J=8.5 Hz,2'-H), 7.12(d,1H,J=8.4 Hz,1'-H); IR ν (neat) 3270, 1730, 1615 cm⁻¹ ; MS m/e 523(M⁺,100%), 508 (M⁺ -CH₃,32%, 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 47%). Theketone amide 4 (163 mg, 0.50 mmol) was dissolved in isoprenyl acetate(10 ml). p-Toluenesulfonic acid (44 mg) was then added and the solutionwas distilled to about two-thirds of the original volume in 7 hrs andwas then stirred at reflux for 12 hrs. Afterwards, the solution wascooled with an ice-water bath and extracted with 50 ml of cooled ether.The ether was washed with a cooled satured sodium bicarbonate and water.The organic phase was dried with anhydrous MgSO₄ and the solvent wasremoved under reduced pressure. The residue was filtered through alumina(15 mm×50 mm, alumina Woehlm neutral, activity II) using a mixture ofbenzene-diethyl ether (3:7 v/v) as eluant. The solvent was removed underreduced pressure and, the residue was purified by flash chromatographyon silica gel. Elution with mixture of EtOAc/hexane (1:4 v/v) yieldedthe N-butyl, N-methyl-11-(3',17'-diacetoxy-estra-1',3',5'(10' ),16'-tetraen-7'α-yl) undecanamide (5) (244 mg, 80%) as colorless oil; ¹H-NMR δ (CDCl₃) 0.92 (s,3H,18'-CH₃), 0.92 and 0.95 (2t,3H,J=7.0Hz,N(CH₂)₃ CH₃), 2.18 (s,3H,17'-OCOCH₃), 2.28(s,3H,3'-OCOCH₃), 2.76 app(d,1H,J=16.1 Hz, part of ABX system, 6'-H, 2.90 and 2.96 (2s,3H,N-CH₃),3.26 and 3.35 (2t_(app),2H,J=7.6 Hz,N-CH₂ --), 5.52 (m,1H,16'-H), 6.80(broad s,1H,4'-H), 6.85 (dd,1H,J₁ =9.1 Hz and J₂ =3.0 Hz,2'-H), 7.27(d,1H,J=9.1 Hz,1'-H); IR ν (neat) 1750, 1635, 1200 cm⁻¹ ; MS m/e 607(M⁺,2%), 565 (M⁺ -COCH₂,100%), 550 (M⁺ -COCH₂ -CH₃,13%), 523 (M⁺-2COCH₃,45%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺,55%), 129 (C₄ H₉ (CH₃)NCOCH₃⁺,38%), 114 (C₄ H₉ (CH₃)NCO⁺,60%), 86 (C₄ H₉ (CH₃)N⁺,25%); EXACT MASScalcd for C₃₉ H₅₇ O₅ N 607.4239, found 607.4234.

N-butyl,N-methyl-11-(16'α-chloro-3'acetoxy-17'-oxo-estra-1',3',5'(10')-trien-7'α-yl)undecanamide (6)

To diacetate amide 5, dissolved in 5 ml of acetone, was added a solutionof sodium acetate (2.6 equivalents) in acetic acid and water (1:11.3v/v) and then, was treated with tertbutyl hypochlorite (1 eq.) preparedfrom t-butanol (4 ml) and Javel water (Javex 6.1%, 50 ml). The clearsolution was warmed to 55° C. and stirred for 1 h. Afterwards, thesolvent was evaporated to dryness. The residue was dissolved in ether(100 ml) and water was added (20 ml). The organic phase was washed withwater, dried with anhydrous MgSO₄ and evaporated to dryness. The residuewas purified by chromatography on silica gel carried out with mixture ofEtOAc/hexane (3:7 v/v) to give the N-butyl,N-methyl-11-(16'α-chloro-3'acetoxy-17'-oxo-estra-1',3',4'(10')-trien-7'α-yl)undecanamide (6) (115 mg, 89%) as colorless oil; ¹ H-NMR δ (CDCl₃) 0.92and 0.95 (2t,3H,J=7.0 Hz,N(CH₂)₃ CH₃), 0.96 (s,3H,18'-CH₃), 2.28(s,3H,3'-OCOCH₃), 2.80 app (d,1H,J=16.6 Hz, part of ABX system, 6'-H)2.90 and 2.96 (2s,3H,N-CH₃), 3.24 and 3.35 (2t_(app),2H,J=7.4 Hz,-N-CH₂--), 4.46 (d,1H,J=6.6 Hz,16'β-H), 6.82 (broad s,1H,4'-H), 6.86(dd,1H,J=9.1 Hz and J₂ =2.6 Hz,2'-H), 7.29 (d,1H,J=9.1 Hz,1'-H); IR ν(neat) 1750, 1640, 1250 cm⁻¹ ; MS m/e 601, 599 (M⁺,24%, 68%), 142 (C₂ H₄CON(CH₃)C₄ H₉ ⁺, 100%), 114 (C₄ H₉ (CH.sub. 3)NCO⁺,93%).

N-butyl,N-methyl-11-(16α-chloro-3',17'β-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 139")

A stirred solution of haloketone amide 6 in anhydrous tetrahydrofuran(THF) (10 ml) under argon was chilled to -70° C. with 2-propanol/dry icebath. A solution of 1.0M of lithium aluminium hybride (2 eq.) was thenadded dropwise. After 30 min, the reaction was allowed to return slowlyat 0° C. for 5 min, then was quenched by the dropwise addition of amixture of THF-EtOAc (5 ml) (1:1 v/v) and acidified at pH˜4 with (10%)HCl. The mixture was stirring for 5 min. at room temperature and thenextracted with EtOAc. The organic phase was washed with water, dried onanhydrous Na₂ SO₄ and evaporated under reduced pressure. The residueincluded two important antiestrogens which were separated bychromatography on silica gel and eluted with a mixture of EtOAc/hexane(4:6 v/v) to give: N-butyl,N-methyl-11-(16'α-chloro-3'17'α-dihydroxy-estra-1',3',5'(10')-trien-7'α-yl)undecanamide ("EM 170") (15 mg, 29%) as colorless oil; analytical samplewas obtained by HPLC purification; ¹ H-NMR δ (CDCl₃, 400 MHz) 0.79(s,3H,18'-CH₃), 0.93 and 0.96 (2t, 3H,J=7.3 Hz,N(CH₂)₃ CH₃), 2.80(2H,J₆,6 =17.1 Hz and J₆,7 =4.5 Hz, Δδ=24.34 (Hz, system ABX, 6'-H),2.94 and 2.99 (2s, 3H,N-CH₃), 3.26 (dd,J₁ =7.6 Hz and J₂ =7.4 Hz) and3.32-3.43 (m)-[2H,-N-CH₂ -], 3.71 (d,1H,J=4.5 Hz,17'β-H), 4.63 (ddd, 1H,J₁₆,15 =10.2 Hz, J₁₆,17 =4.5 Hz and J₁₆,15 3.9 Hz, 16'β-H), 6.50 (d, 1H,J=24 Hz, 3' -OH), 6.60 (d, 1H,J=2.5 Hz, 4'-H), 6.66 (dd,1H,J₁ =8.4 Hzand J₃ =2.5 Hz, 2'-H), 7.14 (d,1H,J=8.5 Hz, 1'-H); IR ν (neat) 3300,1615, 1495 cm⁻¹ ; MS m/e 561,559 (M⁺, 40%, 100%), 523 (M⁺ -HCl, 20%),142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 44%), 114 (C₄ H₉ (CH₃)CNO⁺, 37%); Exact masscalculated for C₃₄ H₅₄ O₃ N³⁵ Cl 559.3785, found 559.3821;

and

-N-butyl, N-methyl-11-(16'α-chloro3',17'β-dihydroxy-estra-1'3',5'(10')-trien-7'α-yl) undecanamide ("EM139") (25 mg, 55%) as a colorless oil; analytical sample was obtained byHPLC purification; 1H-NMR δ (CDCl₃, 400 MHz), 0.81 (s,3H, 18'-CH₃), 0.93and 0.96 (2t, 3H,J=7.3 Hz, (CH₂)₃ CH₃), 2.78 (2H, J₆,6 =16.2 Hz and J₆,7=4.5 Hz, Δ⁵ 24.34 Hz, system ABX, 6'-H), 2.94 and 2.99 (2S, 3H,N-CH₃),3.27 (dd, J₁ =7.6 Hz and J₂ =7.5 Hz) and 3.31-3.45 (M) [2H, --N--CH₂--], 3.86 (dd, 1H, J₁₇,17 -_(OH) =3.4 Hz and J₁₇,16 =5.9 Hz, 17'α-H),4.11 (ddd, 1H, J₁₆,15 =10.8 Hz, J₁₆,17 =5.9 Hz and J₁₆,15 =2.5 Hz,16'β-H), 6.56 (d, 1H, J=19.7 Hz, 3'-OH), 6.61 (d, 1H, J=2.5 Hz, 4'-H),6.66 (dd, 1H, J₁ =8.4 Hz and J₂ =2.6 Hz, 2'-H), 7.13 (d, 1H, J=8.4 Hz,1'-H); IR ν (neat) 3320, 1615, 1490 cm⁻¹ ; MS m/e 551,559 (M⁺, 38%,100%), 523 (M⁺ -HCl, 16%), 142 (C₂ H₄ CON(CH₃)C₄ H₉ ⁺, 80%), 114 (C₄ H₉(CH₃)NCO⁺,76%); Exact mass calculated for C₃₄ H₅₄ O₃ N³⁵ Cl 559.3785,found 559.3825. ##STR21##

EXAMPLE 3

Synthesis of 17β-hydroxy-17α-(12'-iodododecynyl)-Δ⁴ -androsten-3-one("EM 150") (Scheme 3)

3,3-ethylenedioxy-17α-ethynyl-Δ⁵ -androsten-17β-ol (8)

A mixture of ethisterone (7) (9.5 g, 30.4 mmol), ethylene glycol (3.34g, 3 ml, 53.8 mmol) and p-toluenesulfonic acid (50 mg, 0.29 mmol)dissolved in 500 ml of dry benzene was refluxed (Dean-Stark) for 24 hunder nitrogen. Then a mixture of ether and dichloromethane (1:1, 1) wasadded and the resulting solution washed successively with sodiumcarbonate (2×100 ml, 5% aqueous) and with water (4×200 ml). The organicphase was dried, filtered and concentrated to a solid. The residue (9.73g, 90% of crude dioxolane) was used without any further purification inthe next step.

(±)3,3-ethylenedioxy-17β-tetrahydropyranyloxy-17α-ethynyl-66.sup.5androstene (9)

A mixture of crude dioxolane (9.73 g, 27.3 mmol) in dry dichloromethane(500 ml), 2,3-dihydropyran (6.9 g, 7.5 ml, 82.2 mmol), and catalyticpyridinium p-toluenesulfonate (100 mg, 0.4 mmol) was stirred at roomtemperature for 36 h. Then, ether (500 ml) was added and the resultingsolution was washed successively with sodium carbonate (2×100 ml, 5%aqueous) and with water (4×200 ml). The organic phase was dried,filtered and evaporated to give 12.74 g of crude material. The residuewas purified by flash chromatography (hexane:acetone, 95:5) to give 7.7g, 58% of compound 9 along with 2.94 g, 24% of corresponding enone.

(±)3,3-ethylenedioxy-17β-tetrahydropyranyloxy-17α-(12'-iodododecynyl) Δ⁵-androstene (10)

To a solution of butyllithium (2.84 ml of a 1.6M solution in hexane, 4.5mmol) in dry tetrahydrofuran (THF, 45 ml) was added dropwise a solutionof acetylene 9 (500 mg, 1.13 mmol) in dry THF (10 ml) at -40° C. Thereaction mixture was then allowed to warm up to -10° C. and stirred for1 h. At this temperature, a solution of 1,10-diiododecan (2.15 g, 5.4mmol) in dry THF (5 ml) was added in one portion. The cooling bath wasremoved and the reaction mixture was stirred at room temperature for 15h. Then, the solution was diluted with 100 ml of ether and was washedwith water (6×30 ml), dried, filtered and concentrated to an oil. Theresidue was purified by flash chromatography (hexane:acetone, 96:4),followed by preparative thin-layer chromatography (TLC) to give 208 mg,26% of compound 10 (n=10)

17β-hydroxy-17α-(12'-iodododecynyl)-Δ⁴ -androsten-3-one ("EM 150")

To a solution of the oily tetrahydropyranyl ethers (100 mg, 1.4×10⁻⁴mol) in ethanol (5 ml) was added aqueous oxalic acid (2 ml, 2% aqueous).The reaction mixture was heated at reflux for 2.5 h. Then, most of theethanol was evaporated and the residue transferred into a separatoryfunnel with ether (40 ml) and water (20 ml) was washed thoroughly withwater. The ethereal phase was dried, filtered and concentrated to anoil. The residue was purified by column chromatography (toluene:acetone,96.4) to give 63 mg, 77% of iodoenone "EM 150". ##STR22##

EXAMPLE 4

N-butyl, N-methyl-12,13-Bis-(4-hydroxyphenyl)-12-pentadecenoic amide("EM 142", compound 16 with x=10) (Scheme 4)

This synthesis was done as described by Edwards et al. (1988) U.S. Pat.No. 4,760,061.

12,13-Bis-(4-methoxyphenyl)-11-pentadecenol(14)

4'-methoxy-2-ethyl,2-(4-methoxyphenyl) acetophenone 13 (710 mg, 2.5mmol, prepared from desoxyanisoin, ethyl bromide and LDA by a knownmethod) in THF (10 ml) are added, under argon, to Grignard reagentprepared from 11-bromo-tetrahydropyranyl undecanol (6.6 g, 19.7 mmoles)and magnesium (0.6 g, 24.7 mmoles) and THF (10 ml). The mixture wasstirred for 18 hours, then acidified with 1N HCl and extracted threetimes with ether. The organic phase was washed with water (X3), driedover anhydrous magnesium sulfate, and evaporated under reduced pressure.The residue was chromatographed on Silica gel (Kieselgel, 60F254, Merck,0.063-0.200 mm, 100 g). Elution with a mixture of hexane-ethyl acetate(9:1 v/v) gave 12,13-Bis-(4-methoxyphenyl)-tetrahydropyranylpentadecan-1,12-diol (991 mg, 76%) as a mixture of diastereoisomers;colorless oil, IR ν_(max) (neat) 3480, 1600 cm⁻¹ ; ¹ H-NMR (δ, CDCl₃);0.62 (3H, t, J=7.3 Hz, CH₂ CH₃), 2.73 (1H, 2d, J=9.7 Hz, --CHCH₂ CH₃),3.25-4.00 (4H, m, --CH₂ OCHOCH₂ --), 3.76 and 3.79 (6H, 2s, --OCH₃),4.57 (1H, t, J=1.1 Hz, --O₃ --CH--CH₂) and 6.71-7.30 (8H, m,H-Ar)ppm. MSm/e=523 (M⁺ -H₂ O).

The above diastereoisomers (920 mg, 1.8 mmol) dissolved in methanol (30ml) and 5N HCl (5 ml) was refluxed for 1 hour, then collected, andextracted three times with ether. The organic layer was washed withwater, dried over anhydrous magnesium sulfate, evaporated under reducedpressure to dryness and finally chromatographed on silica gel (Kiesegel,60F254, 0.063-0.200 mm, Merck, 100 g). Elution with a mixture ofhexane-ethyl acetate (7:3 v/v) gave12,13-Bis-(4-methoxyphenyl)-11-pentadecenol (710 mg, 65% from compound13), colorless oil, IR ν_(max) (neat), 3340, 1600, 1030 cm⁻¹, UV λ_(max)(log ε)=231 (4.27) nm; ¹ H-NMR (δ, CDCl₃), 0.88 (3H, t, J=7.3 Hz, --CH₂CH₃), 3.30 (1H,t,J=9.7 Hz, --CH--CH₂, CH₃), 3.63 (2H,t, J=6.6 Hz, --CH₂OH), 3.76 and 3.78 (6H, 2s, --OCH₃), 5.51 (1H, t, J=8.8 Hz,1--C.tbd.CH--) and 6.63-7.10 8H, m, H-Ar) ppm; MS m/e=438 (M⁺).

N-butyl, N-methyl-12,12-Bis-(4-methoxyphenyl)-11-pentadecenoic amide(15)

To a cooled solution of alcohol 14 (710 mg, 1.56 mmol) in acetone (17ml) was added Jones' reagent (8N-chromic acid solution, 0.77 ml). After30 minutes, isopropanol (5 ml) was added and the mixture was poured inwater and extracted three times with ethyl acetate. The organic layerwas washed twice with brine, dried over magnesium sulfate and evaporatedto dryness. The crude 12,13-Bis-(4-methoxyphenyl)-11-pentadecenoic acidwas used in the next step without purification. To its solution inanhydrous methylene chloride (4 ml) at -10° C. was added, understirring, triisobutylamine (470 μl, 1.96 mmol) and isobutylchloroformate(280 μl, 2.1 mmol). After 40 minutes, N-methylbutylamine (1.5 ml) wasadded and the mixture was stirred at room temperature during 1 hour.Methylene chloride (50 ml) was added. The organic solution was washedwith 1N HCl, saturated sodium bicarbonate solution and water (3X), driedon magnesium sulfate and evaporated to dryness. The residue was purifiedby "flash chromatography" on silica gel (Kieselgel 60, Merck, unter0.063 mm, 50 g). Elution with a mixture of hexane-ethyl acetate (4:1v/v) gave N-butyl, N-methyl-12,13-Bis (4-methoxyphenyl)-11-pentadecenoicamide (15), (549 mg, 68%) colorless oil; IR ν_(max) (neat), 1640, 1600cm⁻¹ ; UV λ_(max) (log ε)=230 (4.39) nm; ¹ H-NMR (δ, CDCl₃), 0.85-0.98(6H, m, 2-CH₂ CH₃), 2.27 (2H, t, J=7.1 Hz, CH₃ CON), 2.91 and 2.96 (3H,2s, --NCH₃), 3.25-3.36 (3H, m, --NCH₃ -- and CH₃ CH₃ CH-), 3.77 and 3.78(6H, 2s, OCH₃ ), 5.50 (1H, J=7.1 Hz, --C═CH--) and 6.69-7.01 (8H, m,H-Ar) ppm; MS m/e=521 (M⁺).

N-butyl, N-methyl-12,13-Bis-(4-hydroxyphenyl)-12-pentadeconic amide("EM-142", compound 16 with x=10)

To the above dimethoxy amide 15 (117 mg, 0.22 mmol) in CH₂ Cl₂ (1 ml) at0° C. was added, under argon, 1.0 M borane tribromide (675 μl). Thesolution was stirred for 1 hour, then poured into water and extractedwith ether (3×). The organic solution was washed with water, dried onmagnesium sulfate, and evaporated to dryness. The residue was purifiedby "Flash chromatography" on silica gel (Kieselgel 60, Merck, unter0.063 mm, 30 g). Elution with a mixture of hexane-ethyl acetate (4:1v/v) gave N-butyl, N-methyl-12,13-Bis (4-hydroxyphenyl)-12-pentadeconicamide ("EM-142", compound 16 with ×=10) (34 mg, 31%), colorless oil, IRν_(max) (neat) 3300, 1600 cm⁻¹ ; UV ν_(max) (log ε)=235 (4.25) nm; ¹H-NMR (δ, CDCl₃), 0.76 (3H, t, J= 7.3 Hz, --CH₃ CH₃), 0.96 (3H, t, J=7.3Hz, N (CH₂)₃ CH₃), 2.05-2.20 (4H, m, CH₂ -C═C--CH₂ --), 2.35 (2H, t,J=7.0 Hz, --CH₃ CON--), 2.97 and 3.00 (3H, s, --NCH₃), 3.29 and 3.41(2H, 2t, J═7.3 Hz, --N--CH₃ --), and 6.59-7.09 (8H, m, H-Ar) ppm; MSm/e=493 (M⁺). ##STR23##

EXAMPLE 5

N-butyl, N-methyl (ω-2) p-hydroxypohenyl (ω-1)-(hydroxy cyclohexa-4-yl)alkylamide ##STR24##

The compounds synthesized above have been tested and have been found tobe effective inhibitors of the activity of enzymes which catalyze sexsteroid formation. In order to test this inhibition, the effect of theabove-synthesized compounds on the 17β-hydroxysteroiddehydrogenase-catalyzed conversion of estradiol to estrone was observed.The reaction was followed by monitoring-formation of NADH at 340 nm (therate of conversion of the cofactor NAD to NADH varies directly with therate of estradiol conversion to estrone). The ability of compounds ofthe invention to inhibit this reaction is indicative of their ability toinhibit the estrogen-forming reverse reaction because both reactions arecatalyzed by 17β-hydroxysteroid dehydrogenase (Thomas et al., J. Biol.Chem. 258: 11500-11504, 1983).

To test the effect of EM 139, 17β-hydroxysteroid dehydrogenase (17β-HSD)was purified to homogeneity from human placenta. A reaction vessel wasprepared containing 1 μg 17β-HSD, 5 mM NAD, 20 μM 17β-estradiol, and theconcentrations of the test compound EM 139 indicated along the X-axis ofFIG. 1 in 1.0 ml of a mixture of Tris-CHl (50 mM), EDTA (2 mM), NaN₃ (5mM). The pH was 7.5. The reaction was allowed to proceed at 25° C. for15 min. Formation of NADH was measured at 340 nm. As shown by FIG. 1,increasing concentrations of EM 139 significantly inhibited thereaction.

To test the effect of EM 150, 17β-hydroxysteroid dehydrogenase (17β-HSD)was purified to homogeneity from human placenta. A reaction vessel wasprepared containing 1 μg 17β-HSD, 5 mM NAD, 20 μM 17β-estradiol, and theconcentrations of the test compound EM 139 indicated along the X-axis ofFIG. 2 in 1.0 ml of a mixture of Tris-HCl (50 mM), EDTA (2 mM), MaN₃ (5mM). The pH was 7.5. The reaction was allowed to proceed at 25° C. for15 min. Formation of NADH was measured at 340 nm. As shown by FIG. 2,increasing concentrations of EM 150 significantly inhibited thereaction.

To test the effect of EM 142, 17β-hydroxysteroid dehydrogenase (17β-HSD)was purified to homogeneity from human placenta. A reaction vessel wasprepared containing 1 μg 17β-HSD, 5 mM NAD, 20 μM 17β-estradiol, and theconcentrations of the test compound EM 142 indicated along the X-axis ofFIG. 3 in 1.0 ml of a mixture of Tris-HCl (50 mM), EDTA (2 mM), NaN₃ (5mM). The pH was 7.5. The reaction was allowed to proceed at 25° C. for15 min. Formation of NADH was measured at 340 nm. As shown by FIG. 3,increasing concentrations of EM 142 significantly inhibited thereaction.

The terms and descriptions used herein are preferred embodiments setforth by way of illustration only, and are not intended as limitationson the many variations which those of skill the art will recognize to bepossible in practicing the present invention as defined by the followingclaims.

What is claimed is:
 1. A method for inhibiting sex steroid formationcomprising administering to a warm-blooded patient in need of suchinhibition, a therapeutically effective amount of a compound of theformula: ##STR25## wherein the dotted lines represent optional doublebonds; wherein the A-ring is optionally aromatic;wherein R₁, R₂ and R₄are independently selected from the group consisting of hydrogen,hyroxyl, alkylsulfonyl(lower)alkoxy, arylsulfonyl(lower)alkoxy, halogen,lower alkyl, lower alkoxy, lower alkylsilyl, amino and nitro; wherein R₃is selected from the group consisting of hydrogen, hydroxyl, halogen,lower alkyl, methoxy, ethoxy, propoxy, hydroxyethoxy, lower alkoxy,acetoxy, propionyloxy, butyryloxy, oenanthoyloxy, cypionoyloxy,trans-4-n-butyl-cyclohexanecarbonoyloxy, (C₂ -C₂₀)alkanoyloxy, loweralkoxy carbonyloxy, carboxy, (C₃ -C₂₀)alkenoyloxy, (C₃ -C₂₀)alkynoyloxy,(C₇ -C₁₀)aroyloxy or a divalent common species formed jointly byR₃.sbsb.(α) and R₃.sbsb.(β), said divalent common speices being selectedfrom the group consisting of ═O, ═S, ═NR₃₆ or ═NOR₃₆ wherein R₃₆ ishydrogen or lower alkyl; wherein R₅ and R₁₀ are absent or selected fromthe group consisting of hydrogen and lower alkyl; wherein R₆ is selectedfrom the group consisting of hydrogen, halogen, lower alkyl, amino andnitrile; wherein R₇ is in α position and is hydrogen, hydroxyl, halogen,lower alkyl, lower alkoxy, lower alkylsilyl, amino, nitrile, nitro,nitroso, alkylsulfonyl, arylsulfonyl, lower alkylamino, diloweralkylamino, or is represented by the formula A¹ -[Y-A¹¹ ]_(u) --X--R₂₁,wherein: u is an integer from 0 to 5; wherein A¹ and A¹¹ may be the sameor different and are selected from the group consisting of a bond,straight- or branched-chain alkylene, straight- or branched-chainalkynylene, straight- or branched-chain alkenylene, andfluoro-substituted analogs of the foregoing, wherein R¹ and A¹ 1together have a total of from 3 to 30 carbon atoms, and Y is selectedfrom the group consisting of --O--, --S--, --Se--, --SO--, --SO₂ --,--CO--, --NR₂₂ --, --SiR₂₂ R₂₂ --, --CR₂₂ OR₂₂ --NR₂₂ CO--, --NR₂₂ CS--,--CONR₂₂ --, --CSNR₂₂ --, --COO--, --COS--, --SCO--, --CSS--, --SCS--,--OCO-- and phenylene (R₂₂ being hydrogen or lower alkyl); R₂₁ isselected from the group consisting of hydrogen, straight- orbranched-chain lower alkyl, lower alkenyl or lower alkynyl, (C₃-C₇)cycloalkyl, halogeno(lower)alkyl, carboxy(lower)alkyl,(lower)alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀)aryl, (C₇ -C₁₁)arylalkyl,di(lower)alkylamino(lower)alkyl and fluoro-substituted analogs of theforegoing, and wherein X is --CONR₂₃ --, --CSNR₂₃ --, --NR₂₄ CO--,--NR₂₄ CS--, --NR₂₄ CONR₂₃ --, ##STR26## --SO₂ NR₂₃ --, --CSS--,--SCS--, --NR₂₃ --, --(NO)R₂₃ --, --(PO)R₂₃ --, --NR₂₄ CO--, --NR₂₄ SO₂--, --S--, --SO-- or --SO₂ --, (wherein R₂₃ is selected from the groupconsisting of hydrogen, lower alkyl, and a species which, together withR₂₁, forms a saturated or unsaturated heterocyclic ring having at leastone nitrogen atom and, optionally, a second heteroatom selected from thegroup consisting of oxygen, sulfur, silicon, selenium, nitrogen andfluoro-substituted analogs of the foregoing, wherein R₂₄ is hydrogen orlower alkyl and wherein R₂₅ is hydrogen, nitrile or nitro) (XR₂₁ mayform a tetrazole ring);wherein R₁₁ is selected from the group consistingof hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C₆ -C₁₀)aryl,alkylsulfonyl, arylsulfonyl, a substituted 5-to-7 member heterocyclicring having at least one heteroatom (selected from oxygen, sulfur,silicon, selenium, nitrogen), --(CH₂)_(s) W (wherein W is nitrile,hydroxyl, azido, nitroso, nitro, thionitrile, halogen, alkylsulfonyl orarylsulfonyl, and s is an integer from 1 to 6), OR₂₆ (wherein R₂₆ ishydrogen, lower alkyl or (C₆ -C₁₀)aryl), DR₂₇ (wherein D is --Se--,--NR₂₆, --S-- or --O--, and R₂₇ is hydrogen, lower alkyl), ═O, ═S, ═Se,═NR₂₈ (wherein R₂₈ is hydrogen or lower alkyl; wherein R₁₂ and R₁₃ areindependently hydrogen or lower alkyl; wherein R₁₄ is selected from thegroup consisting of hydrogen, hydroxyl, nitrile, nitro, nitroso,halogen, lower alkyl, lower alkoxy, lower alkyseleno, lower alkylaminoor diloweralkylamino; or R₁₄ and R₁₅ together are --CH₂ --, --CHX--,--CX₂ --, (X=halogen, carboxyl or alkoxycarbonyl), --O--, --S--,--Se--, >N-CN, >NR₂₉ and >NCO₂ R₂₉ wherein R₂₉ is hydrogen or loweralkyl; wherein R₁₅ is selected from the group consisting of hydrogen,hydroxyl, nitro, nitroso, halogen, lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy, lower alkylseleno, lower alkylamino,di(lower)alkylamino, nitrile, azido, arylseleno, AXR₂₁, A₁ -[Y-A¹¹ ]_(u)-X-R₂₁ or R₁₅ and R₁₆ together are --CH₂ --, --CHX--, --CX₂ --,(X=halogen, carboxyl or alkoxycarbonyl), --O--, --S--, --Se--, >N-CN,>NR₂₉ and >NCO₂ R₂₉ wherein R₂₉ is hydrogen or lower alkyl; wherein R₁₆is selected from the group consisting of hydrogen, nitroso, halogen,lower alkyl, carboxyl, lower alkoxy, lower alkylseleno, loweralkylamino, nitrile, azido, arylseleno, lower alkylseleno,di(lower)alkylamino, AXR₂₁, or A¹ -[Y-A¹¹ ]_(u) -X-R₂₁, R₁₆.sbsb.(α) andR₁₆.sbsb.(β) together are ═CG₂, where G is hydrogen, halogen, loweralkyl, lower alkenyl, lower alkynyl, nitrile, alkoxycarbonyl,alkylcarbonyl and carboxyl; wherein R₁₇.sbsb.(α) is selected from thegroup consisting of hydrogen, hydroxyl, lower alkyl,halogeno(lower)alkyl, AXR₂, A¹ -[Y-A¹¹ ]_(u) X-R₂₁, B¹ -T-R₃₀ wherein:B¹ is straight- or branched-chain (C₁ -C₁₂)alkylene, (C₂-C₁₂)alkynylene, (C₂ -C₁₂)alkenylene; T is --O--, --NR₃₁, --Se--, --S--or S-S and R₃₀ and R₃₁ are independently hydrogen, lower alkyl, or R₃₀and R₃₁, together are (C₃ -C₇)cycloalkyl, (C₅ -C₇)cycloalkenyl, (C₃-C₇)cycloalkyl or (C₅ -C₇)cycloalkenyl having one or more hydrogen atomsreplaced by halogen atoms, --HC═CHR₃₂ and --C.tbd.CR₃₃ wherein: R₃₂ andR₃₃ are independently hydrogen, halogen, tri(lower)alkylsilyl, carboxyl,carbonyl, lower alkoxy, nitrile, sulfinyl lower alkyl, AXR₂₁, A¹ -[Y-A¹¹]_(u) -X-R₂₁ or a species represented by the formula: ##STR27## whereinn and m are independently 0 to 6 and Q is --Se--, --SiH₂ --, --S--,--O-- or --NR₃₄ -- wherein R₃₄ is hydrogen, lower alkyl or (C₁-C₇)alkanoyl; or a species represented by the formula: ##STR28## whereinq is --CH₂ --, --S--, --O-- or --NR₃₅ -- wherein R₃₅ is hydrogen orlower alkyl;wherein R₁₇.sbsb.(β) is selected from the group consistingof hydrogen, hydroxyl, halogen, 1-oxo-2-propoynyl, 1-hydroxy-2-propynyl,alkoxy, (C₁ -C₁₇)alkanoyloxy, (C₃ -C₇)alkenyloxy, (C₃ -C₇)alkynoyloxy,alkenyloxy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxycycloalkyloxy, alkylsilyloxy and a divalent common species formedjointly by R₁₇.sbsb.(α) and R₁₇.sbsb.(β), said divalent common speciesbeing selected from the group consisting of ═O, ═S, ═NR₃₆ or ═NOR₃₆wherein R₃₆ is hydrogen or lower alkyl, wherein at least one or R⁷, R¹⁶or R¹⁷ is A¹ -[Y-A¹¹ -]_(u) XR²¹.
 2. The method of claim 1 whereinandrogen formation is inhibited.
 3. The method of claim 1 whereinestrogen formation is inhibited.
 4. The method of claim 1 wherein saidcompound is administered in the form of parenteral controlled-releasecomposition at a daily release does of from 5 to 1250 mg per day.
 5. Themethod of claim 1 where said compound is administered in the form oforal composition at a daily release dose of from 5 to 1250 mg per day.6. A method according to claim 1 wherein the testicular or ovariansecretions of the patient are inhibited by surgical or chemical means.7. The method of claim 1 wherein said compound is ##STR29##
 8. A methodof claim 1 wherein said compound is ##STR30##
 9. The method of claim 1wherein said compound is ##STR31##
 10. The method of claim 1, whereinsaid compound ##STR32##
 11. A pharmaceutical composition comprising apharmaceutically effective diluent or carrier and a therapeuticallyeffective amount of a compound of the formula: ##STR33## wherein thedotted lines represent optional double bonds; wherein the A-ring isoptionally aromatic;whrein R₁, R₂ and R₄ are independently selected fromthe group consisting of hydrogen, hydroxyl, alkylsulfonyl(lower)alkoxy,arylsulfonyl(lower)alkoxy, halogen, lower alkyl, lower alkoxy, loweralkylsilyl, amino and nitro; wherein R₃ is selected from the groupconsisting of hydrogen, hydroxyl, halogen, lower alkyl, methoxy, ethoxy,propoxy, hydroxyethoxy, lower alkoxy, acetoxy, propionyloxy, butyryloxy,oenanthoyloxy, cypionoyloxy, trans-4-n-butyl-cyclohexanecarbonoyloxy,(C₂ -C₂₀) alkanoyloxy, lower alkoxy carbonyloxy, carboxy, (C₃ -C₂₀)alkenoyloxy, (C₃ -C₂₀) alkynoyloxy, (C₇ -C₁₀) aroyloxy or a divalentcommon species formed jointly by R₃.sbsb.(α) and R₃.sbsb.(β), saiddivalent common species being selected from the group consisting of ═O,═S, ═NR₃₆ or ═NOR₃₆ wherein R₃₆ is hydrogen or lower alkyl; wherein R₅and R₁₀ are absent or selected from the group consisting of hydrogen andlower alkyl; wherein R₆ is selected from the group consisting ofhydrogen, halogen, lower alkyl, amino and nitrile; wherein R₇ is in αposition and is hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy,lower alkylsilyl, amino, nitrile, nitro, nitroso, alkylsulfonyl,arylsulfonyl, lower alkylamino, dilower alkylamino, or is represented bythe formula A¹ -[Y-A¹¹ ]_(u) --X--R₂₁, wherein: u is an integer from 0to 5; wherein A¹ and A¹¹ may be the same or different and are selectedfrom the group consisting of a bond, straight- or branched-chainalkylene, straight- or branched-chain alkynylene, straight- orbranched-chain alkenylene, and fluoro-substituted analogs of theforegoing, wherein A¹ and A¹¹ together have a total of from 3 to 30carbon atoms, and Y is selected from the group consisting of --O--,--S--, --Se--, --SO--, --SO₂ --, --CO--, --NR₂₂ --, --SiR₂₂ R₂₂, --CR₂₂OR₂₂ --, --NR₂₂ --CO--, --NR₂₂ CS--, --CONR₂₂ --, --CSNR₂₂ --, --COO--,--COS--, --SCO--, --CSS--, --SCS--, --OCO-- and phenylene (R₂₂ beinghydrogen or lower alkyl); R₂₁ is selected from the group consisting ofhydrogen, straight- or branched-chain lower alkyl, lower alkenyl orlower alkynyl, (C₃ -C₇ ) cycloalkyl, halogeno(lower)alkyl,carboxy(lower)alkyl, (lower) alkoxycarbonyl(lower)alkyl, (C₆ -C₁₀) aryl,(C₇ -C₁₁) aryl-alkyl, di(lower) alkylamino(lower)alkyl andfluoro-substituted analogs of the foregoin, and wherein X is --CONR₂₃--, --CSNR₂₃ --, --NR₂₄ CO--, --NR₂₄ CS--, --NR₂₄ CONR₂₃ --, ##STR34##--SO₂ NR₂₃ --, --CSS--, --SCS--, --NR₂₃ --, --(NO)R₂₃ --, --(PO)R₂₃ --,--NR₂₄ COO--, --NR₂₄ SO₂ --, --S--, --SO-- or --SO₂ --, (where R₂₃ isselected from the group consisting of hydrogen, lower alkyl, and aspecies which, together with R₂₁, forms a saturated or unsaturatedheterocyclic ring having at least one nitrogen atom and, optionally, asecond hereroatom selected from the group consisting of oxygen, sulfur,silicon, selenium, nitrogen and fluoro-substituted analogs of theforegoing, where R₂₄ is hydrogen or lower alkyl and wherein R₂₅ ishydrogen, nitrile or nitro) (XR₂₁ may form a tetrazole ring);wherein R₁₁is selected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, (C₆ -C₁₀) aryl, alkylsulfonyl, arysulfonyl, asubstituted 5-to-7 member heterocyclic ring having at least oneheteroatom (selected from oxygen, sulfur, silicon, selenium, nitrogen),--(CH₂)_(s) W (wherein W is nitrile, hydroxyl, azido, nitroso, nitro,thionitrile, halogen, alkylsulfonyl or arylsulfonyl, and s is aninterger from 1 to 6), OR₂₆ (wherein R₂₆ is hydrogen, lower alkyl or (C₆-C₁₀) aryl), DR₂₇ (wherein D is --Se--, --NR₂₆, --S-- or --O--, and R₂₇is hydrogen, lower alkyl), ═O, ═S, ═Se, ═NR₂₈ (wherein R₂₈ is hydrogenor lower alkyl; wherein R₁₂ and R₁₃ are independently hydrogen or loweralkyl; wherein R₁₄ is selected from the group consisting of hydrogen,hydroxyl, nitrile, nitro, nitroso, halogen, lower alkyl, lower alkoxy,lower alkyseleno, lower alkylamino or diloweralkylamino; or R₁₄ and R₁₅together are --CH₂ --, --CHX--, --CX₂ --, (X=halogen, carboxyl oralkoxycarbonyl), --O--, --S--, --Se--, >N-CN, >NR₂₉ and >NCO₂ R₂₉wherein R₂₉ is hydrogen or lower alkyl; wherein R₁₅ is selected from thegroup consisting of hydrogen, hydroxyl, nitro, nitroso, halogen, loweralkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylseleno,lower alkylamino, di(lower) alkylamino, nitrile, azido, arylseleno,AXR₂₁, A₁ -[Y-A¹¹ ]_(u) --X--R₂₁ or R₁₅ and R₁₆ together are --CH₂ --,--CHX--, --CX₂ --, (X=halogen, carboxyl or alkoxycarbonyl), --O--,--S--, --Se--, >N-CN, >NR₂₉ and >NCO₂ R₂₉ wheren R₂₉ is hydrogen orlower alkyl; wherein R₁₆.sbsb.(α) is selected from the group consistingof chlorine, fluorine, bromine, iodine, R₁₆.sbsb.(α) together with orR₁₆.sbsb.(β) is =CG₂. wherein R₁₇.sbsb.(α) is selected from the groupconsisting of hydrogen, hydroxyl, lower alkyl, halogeno(lower)alkyl,AXR₂, A¹ -[Y-A¹¹ ]_(u) X--R₂₁, B¹ -T-R₃₀ wherein: B¹ is straight- orbranched-chain (C₁ -C₁₂) alkylene, (C₂ -C₁₂) alkynylene, (C₂ -C₁₂)alkenylene; T is --O--, --NR₃₁, --Se--, --S-- or S--S and R₃₀ and R₃₁are independently hydrogen, lower alkyl, or R₃₀ and R₃₁, together are(C₃ -C₇) cycloalkyl, (C₅ -C₇) cycloalkyenyl, (C₃ -C₇) cycloalkyl or (C₅-C₇) cycloalkenyl having one or more hydrogen atoms replaced by halogenatoms, --HC═CHR₃₂ and --C.tbd.CR₃₃ wherein: R₃₂ and R₃₃ areindependently hydrogen, halogen, tri(lower)alkylsily, carboxyl,carbonyl, lower alkoxy, nitrile, sulfinyl lower alkyl, AXR₂₁, A¹ -[Y-A¹¹]_(u) --X--R₂₁ or a species represented by the formula: ##STR35##wherein n and m are independently 0 to 6 and Q is --Se--, --SiH₂ --,--S--, --O-- or --NR₃₄ --wherein R₃₄ is hydrogen, lower alkyl or (C₁-C₇)alkanoyl; or a species represented by the formula: ##STR36## whereinq is --CH₂ --, --S--, --O-- or --NR₃₅ -- wherein R₃₅ is hydrogen orlower alkyl;wherein R₁₇.sbsb.(β) is selected from the group consistingof hydrogen, hydroxyl, halogen, 1-oxo-2-propynyl, 1-hydroxy-2-propynyl,alkoxy, (C₁ -C₇)alkanoyloxy, (C₃ -C₇)alkenoyloxy, (C₃ -C₇)alkynoyloxy,alkenyloxy, cycloalkenyloxy, 1-alkyloxy-alkyloxy, 1-alkyloxycycloalkyloxy, alkylsilyloxy and a divalent common species formedjointly by R₁₇.sbsb.(α) and R₁₇.sbsb.(β), said divalent common speciesbeing selected from the group consisting of ═O, ═S, ═NR₃₆ or ═NOR₃₆wherein R₃₆ is hydrogen or lower alkyl, wherein at least one or R⁷, R¹⁶or R¹⁷ is A¹ -[Y-A¹¹ -]_(u) XR²¹.